Azacycloalkanes



United States Patent 2,742,475 YAZACYGLOALKANES Karl Holimaun, Binningen, Ernst Sury, Basel, and Eugen Tagmann, Therwil, Switzerland, v Pharmaceutical Products, Inc.,-S ummit, N. J.

N 0. Drawing. Application February 2%), 49 53,

SerialNo. 338,152

t r im tp pn i a ms zerlan f .February'26,.1952

s Claims. c1, gang-293.4

The present invention relates i tothe manufacture of 3-aryl-3'pyridyl-mono-oxo-l-azacycloalkanes of the formula Y Pyiidyl (CH2) 1. Aryl X1: o=x2 and salts and quaternary compounds thereof,'for example,

their alkyl pyridinium salts. In the above formula n represents-the whole number 1 or 2', R represents hydrogen oranorganic radical such as an alkyl group, especially And represents, for example,

or substituted hydroxyl oramino groups or halogen atom's.

The new compounds possess. valuable pharmacological properties and can be used as medicaments, especially as anti-convulsive agents.

The aforesaid 3-aryl-3 -pyridyl-mono-oxo-l-azacycloalkanes are made bytreating a compound of the formula Aryl "R;

Pyridyl (CHfin Rz in which one of the radicals R1 and R2 represents a radical convertible by reduction .into the group VCH:1.QNHR,

fespeeiany a nitrile group, and. the other of those radicals represents acarboxyl group 011 an. esterified carboxyl group,iaiid it and R have themeanings given'abo've, with a "reducing agent ltoform a cyclic lactam. The reduction is advantageouslycarriedout with hydrogen in. the presence 'of a cfataiysts'uch, for example, as, Raney nickel with the addition of ammonia in the presence-of a solvent such'as "alcohol;

in' which h a'nd R' have the "of the two radicals Yr and'Yzrepresentsan oxygen' atom -aiicfth-dtlier represents a group exchangeable for two an alternativetprocess, in a compoundof the formula Pyridyl -'('G' alli" Aryl meanings given above and one Hydrogen atoms by means'of a reducing agent, for exam- 'pl e, an oxygen or sulfur atom, this last mentioned radical is placed by2' hydrogen atoms by reaction with a reductng'agent. The'process may" be carried out, for example,

assignors to Ciba manner the free pyridine or pyridinium bases. latter salts can be made by reaction with acids salts. From the latter therecan be obtained (2")-5-oxo-pyrrolidine of the formula by treating an aryl-pyridyl-mono-oxo-mono-thio-keto-lazacycloalkane -WithQRaney nickel in the presence of a solvent. w 7 i Azacycloalkanes containingno substituent at the ring nitrogen atom and obtained by the'proces's can be substi tu'ted subsequently in the l-position, such as by reaction with a reactive ester of an alcohol, with an aliphatic dia'z ocompound, especially .diazo-rnethane or reactive acid derivatives such as acid halides or anhydrides. Reactive esters ofalcohols are especially those of strong organic or inorganic acids, such as hydrohalic acids or organic sulfonic acids, such as hydrochloric acid or paratoluene sulionic acid. The aforesaid subsequent substitution is advantageously carried out in the presence of a condensing agent, which is capable of forming metal compounds with azacycloalkanes, such as alkali or alkaline earth metals, for example, sodium, lithium, calcium, or their amides, hydrides, hydrocarbon compounds or alcoholates, for example,, s odamide, sodium. hydride, lithium butyl, potassium phenyl, lithium phenyl, potassium tertiary' butylate or potassium tertiary amylate.

When in the foregoing reactions compounds containing no substituentat the pyridine nitrogen atom are obtained,

they may subsequently be quaternated. As quaternatiug agents there are used especially reactive esters of alcohols, for example, alkyl halides, such as. methyl or ethyl chloride, bromide-or iodide, and also dialkyl sulfates, such as dimethyl sulfate or diethyl sulfate, alkylor arylsulfonic acid esters such as paratoluene sulfonic acidmethyl ester.

' Depending on the procedureused there are; obtained the new compounds in the'form of the'free bases or their in the usua B am-th which are suitable for making salts intended for therapeutic use, such, for example, as hydroha'lic. acids, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid, acetic aid, propionic acid, oxalic acid, malonic acid, succinic acid, malic acid, methane sulfonic acid, ethane sulfonic acid, hydroxyethane sulfonic acid; benzene sulfonic acid or toluene sulfonic acid or therapeutically active acids.

The following examples illustrate, the invention, the parts being by weight unless otherwise stated, and the relationship of parts by weight to parts by volume being the same as that of the gram to the cubic centimeter:

. V Example 1 ':19Q,parts of B-phenyl-B-pyridyl-(Z)-,8-cyano-pr0pionic acid ethyl ester are dissolved in 260 parts by volumefof absolute alcohol and shaken with Raney nickel with the addition of ammonia at 50-60 C. in an atmosphere of hydrogen at an initial pressure of atmospheres gauge pressure until the pressure becomes constant. The catalyst is then separated by filtration, the solvent is evaporated under reduced pressure, and the residue is recrystallized from acetone. The resulting melts at 158-159 C. and forms colorless prisms.

The fi-phenyl-,8-pyridyl-(2)-,B-cyano-propionic acid ethyl ester used as starting material can be'made by condens ing 149 parts of phenyl-pyridyl-(Z) acetic acid nitrile with 150 parts of bromacetic acid ethyl ester in the pres- V smears ence of 34 parts of sodamide as condensing agent, 650 parts by volume of absolute toluene being used as solvent.

Example 2 43 parts of 3-phenyl-3-pyridyl-(2')-5-oxo-pyrrolidine are dissolved in 400 parts by volume of tetrahydrofurane and boiled with 25 parts of dimethyl sulfate for several hours under reflux. After reprecipitation from a mixture of methanol and ethyl acetate, the 3-phenyl-3-pyridyl- (2)-5-oxo-pyrrolidine methosulfate of the formula /CH3 N-SOACH3 Oi N is an easily water-soluble, hygroscopic glassy product.

Example 3 130 parts of 'y-phenyly-pyridyl-(2)- -cyanobutyric acid methyl ester, 50 parts of Raney nickel and 450 parts by volume of absolute alcohol are treated in a hydrogenating autoclave with dry ammonia gas, and then agitated with hydrogen at an initial 60 atmospheres gauge pressure at a temperature of 40-50 C. for 24 hours until the absorption of hydrogen ceases. The reaction mixture is heated to the boil on the water bath, the catalyst is separated by filtration, the alcoholic solution is cooled, and the 3-phenyl-3-pyridy1-(2)-6-oxo-piperidine of the formula which crystallizes out is separated by filtration. It melts at l83186 C. after recrystallization from alcohol. The hydrochloride is prepared by dissolving the base in ethyl acetate and introducing gaseous hydrochloric acid. It melts at 2l5-222 C. after recrystallization from methanol with the addition of ethyl acetate.

The 'y-phenyl y-pyridyl-(2)-v-cyano butyric acid methyl ester used as starting material and boiling at 187-190 C. under 0.4 mm. pressure can be made, for example, from 194 parts by weight of phenyl-piperidyl-(Z)-acetic acid nitrile by condensation with 101 parts by Weight of acrylic acid methyl ester in 200 parts by volume of dioxane as solvent and parts by volume of trimethyl-benzylammonium hydroxide as condensing agent.

Example 4 38.2 parts of 'y-(parachlorophenyl)-'y-pyridyl-(2)--ycyano-butyric acid methyl ester, 20 parts of Raney nickel and 500 parts by volume of absolute alcohol are saturated with ammonia gas in a hydrogenating autoclave for two minutes and then agitated with hydrogen at an initial 50 atmospheres gauge pressure for 17 hours at 45-50" C. until the absorption of hydrogen ceases. When the reaction is finished the catalyst is separated by filtration, the alcohol is distilled off under reduced pressure, and the residue consisting of S-(parachlorophenyl) -3-pyridyl-(2')- 6-oxo-piperidine of the formula is recrystallized from ethyl acetate with the addition of ligroin. It melts at l89193 C. The hydrochloride obtainable therefrom as described in Example 3, melts at 240250 C. after recrystallization from methanol with the addition of a small amount of water.

The 7 (parachlorophenyl) 'y pyridyl (2) 'y cyano-butyric acid methyl ester boiling at 187192 C. under 0.8 mm. pressure used as starting material in this example can be made for example, by condensing 68.7 parts by weight of parachlorophenyl-pyridyl-(2)-acetic acid nitrile with 31 parts by weight of acrylic acid methyl ester in the presence of 25 parts by volume of trimethylbenzyl-ammonium hydroxide as catalyst and, for example, 150 parts by volume of dioxane as solvent.

Example 5 20 parts of Raney nickel are added to 33.7 parts of a-phenyl-a-pyridyl-(2)w'cyano-butyric acid methyl ester dissolved in 450 parts by volume of absolute alcohol, and dry ammonia gas is introduced under a gauge pressure of 8 atmospheres for 2 minutes into the mixture in a high pressure hydrogenating autoclave. The reaction mixture is then agitated for 7 hours with hydrogen under an initial gauge pressure of 50 atmospheres until the reaction is finished. The catalyst is separated by filtration, the solvent is evaporated under reduced pressure, and the residue is recrystallized from alcohol with the addition of ethyl acetate and ligroin. The resulting 3-phenyl-3-pyridyl- (2')-2-oxo-piperidine of the formula melts at 167-170 C.

The hydrochloride thereof is prepared as described in Example 3 and melts at 186193 C. after recrystallization from methanol with the addition of ethyl acetate.

The a-phenyLa-pyridyl-(Z) q-cyano-butyric acid methyl ester used as starting material in this example and melting at 69-71" C. can be prepared, for example, from 42 parts by Weight of phenyl-pyridyl-(2)-acetic acid methyl ester by condensation with 12 parts by weight of acrylic acid nitrile in the presence of 5 parts by volume of trimethylbenzyl-ammonium hydroxide as catalyst and 150 parts by volume of dioxane as solvent at a reaction temperature of -90 C. followed by recrystallization of the reaction product from ethyl acetate with the addition of ligroin.

Example 6 parts of 3-phenyl-3-pyridyl-(2)-2,5-dioxopyrrolidine are dissolved in 400 parts by volume of dry pyridine and refluxed at -130 C. for 2 hours with 200 parts of finely powdered phosphorus pentasulfide. After cooling, the reaction mixture is poured into ice water and the red oil extracted with chloroform or ethyl acetate or ether. The extract is washed with a dilute solution of sodium carbonate and then with water and the solvent then evaporated and the residue recrystallized, e. g. from a mixture of area-A75 .5 v ether and petroleum ether. The .3.-phenyl;3;pyridyl (2.

is thus obtained in the form of yellow prismsrnelting at 125126'C.

15.7 parts of 3-phenyls3-pyridyl-(2f)-2-oxo-5-thio-keto- ,pyrrolidineareboiled I under reflux. for 3- hours with 1 150 parts 'ofikaney nickel in 300 parts; by ,volume of methanol. The nickel is then removed by filtration, the solvent evaporated under reduced pressure and the residue recrystallized from acetone. The resulting 3-phenyl-3-pyridyl-(2)-2- oxopyrrolidine of the formula form colorless prisms which melt at 167-168 C.

The 3-phenyl-3-pyridyl-(2)-2,5-dioxo-pyrrolidine used 7 as starting material is described and claimed in application of Karl Hoffmann and Ernst Sury Ser. No. 333,826 filed January 28, 1953, for Dioxo-Pyrrolidines. It can be obtained as follows:

115 parts by weight of 2-phenyl 2-pyridyl-(2)-butane- 1:4-diacid-mononitrile-(1) are dissolved with heating in 250 parts by volume of concentrated aqueous ammonia. The solution is evaporatedto a syrupy consistency in-a water pump vacuum and then carefully heated under normal pressure to a maximum of 260 C. Ammonia and water are briskly evolved in this operation. When the evolution of ammonia is complete, the whole is allowed to cool and the imide produced dissolved in methanol, filtered through carbon, the solvent evaporated to the commencement of crystallization and in this manner 104 parts by weight obtained of 3-phenyl-3-pyridyl-(2')-2:5- dioxo-pyrrolidine of the formula It melts at 128 C. and forms colorless prisms which dissolve in concentrated ammonia, in sodium carbonate solution and in hydrochloric acid. I

The aforementioned 2-phenyl-2-pyridyl-(2')-butane- 1:4-diacid-mononitrile-(1) of decomposition point 97- 108 C. can be prepared, for example, by alkaline hydrolysis of 89 parts by weight of 2-phenyl-2-pyridyl-(2')- butane-1:4-diacid-monoethyl ester mononitrile-(l) dissolved in 250 parts by volume of methanol by means of 28 parts by weight of potassium hydroxide in 50 parts by volume of water, the latter melts at 87-88 C., boils at 180-183" C. under 0.1 mm. pressure and can be pro duced by condensation of 149 parts by weight of phenylpyridyl-(2)-acetic acid nitrile with 150 parts by weight by bromacetic acid ethyl ester in the presence of 34 parts by weight of sodamide as condensing agent.

Example 7 23.8 parts of 3-phenyl-3-pyridyl+(2f) SmXo-pyrroIidine 'are dissolved in 250parts by volumegof absolute toluene,

boiledwhilestirringlfor 4 hours atv 1:20-130.C., with .43 parts of pulverized sodamide, and then cooled. to.60 C. There are then added. dropwiseat 60-80 C. in the course of 15 minutes 13 parts of dimethyl carbamic acid chloride, dissolved in J50 partsby volume of toluene and the whole then stirred for 4 hours at -120 C.

After cooling, activated carbon is I, added, the toluene solution filtered, the filtrate evaporated under reduced pressure, and the residue recrystallized from acetone.

The 1 dirnethyl-carbamyl-3-phenyl-3-pyridyl-(2)-5-oxo pyrrolidine of the tormula O iQ 0N(C H3): is obtained in very good yield, and forms colorless prisms which melt at 151.5-152 C.

Example 8 7.93 parts by weight of 3-phenyl-3-pyridyl-(2')-2-oxopyrrolidine are dissolved in 100 parts by volume of absolute toluene, heated while stirring for 2 hours at C. with 1.4 parts by weight of sodamide, and then cooled to 40 C.' There are then added dropwise in the course of 10 minutes 40 parts by weight of dimethyl-carbamic acid chloride, dissolved in 10 parts by volume of toluene, and the whole then stirred for 3 hours at120 C. .After cooling, the toluene solution is washed with water, dried with calcium chloride, and the residue dis tilled under reduced pressure. The resulting l-dimethylcarbamyl-3-ph-enyl-3-pyridyl-( 2')-2-oxo-pyrrolidine of the formula 7 CI ON ()C Ha): boils at 236-238 C. under 0.2 mm. pressure.

Example 9 in which n is an integer selected from the group consisting of l and 2, R is a member selected from the group consisting of phenyl and halogenophenyl, and one of X1 and X2 represents an oxygen atom and the other represents two hydrogen atoms. V

2. 3-phenyl-3-pyridyl-(2')-2-oxo-pyrrolidine. t

3. 3-phenyl-3-pyridyl- 2 -5-oxo-py1'rolidine.

4. 3 -pheny1-3-pyridyl-(2)-5-0xo-pyrro1idine quaternary ammonium salts.

5 3-pheny1-3-pyridyl-(2') -6-oxo-piperidine.

6. 3-phenyl-3-pyridyl- (2' -2-oxo-piperidine.

7. 3 (p chlorophenyl) 3-pyridyl-(2')-6-oxo-piperidine.

8. 3 phenyl 3 pyridyl-(Z')-2-oxo-5-thio-keto-pyrrolidine.

References Cited in the file of this patent UNITED STATES PATENTS 2,524,643 Walter et a1 Oct. 3, 1950 2,555,353 Lucas et al. June 5, 1951 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3-R--PYRIDYL-(2'')-MONOXO-1-AZACYCLOALKANES, THE SALTS, AND THE QUATERNARY AMMONIUM COMPOUNDS THEREOF, WHICH IN THE FORM OF THE FREE BASE CAN BE REPRESENTED BY THE FOLLOWING FORMULA: 